Read this Patient Information before you start to use XOPENEX Inhalation Solution Concentrate and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is XOPENEX Inhalation Solution Concentrate?

XOPENEX Inhalation Solution Concentrate is an inhaled prescription medicine used for the treatment or prevention of bronchospasm in people 6 years of age and older.

XOPENEX Inhalation Solution Concentrate has not been shown to be safe and effective in children younger than 6 years of age.

Do not use XOPENEX Inhalation Solution Concentrate if you are allergic to levalbuterol, racemic albuterol, or any of the ingredients in XOPENEX. See the end of this leaflet for a complete list of ingredients in XOPENEX Inhalation Solution Concentrate.What should I tell my doctor before using XOPENEX Inhalation Solution Concentrate?Before you use XOPENEX Inhalation Solution Concentrate, tell your doctor if you have:
• had an allergic reaction to levalbuterol or racemic albuterol
• heart problems
• high blood pressure
• seizures
• diabetes
• thyroid problems
• any other medical conditions
• are pregnant or planning to become pregnant. It is not known if XOPENEX Inhalation Solution Concentrate will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
• are breastfeeding or plan to breastfeed. It is not known if XOPENEX Inhalation Solution Concentrate passes into your breast milk. You and your doctor should decide if you will use XOPENEX Inhalation Solution Concentrate or breastfeed. You should not do both.

Tell your doctor about all the medicines you take including prescription and over-the-counter medicines, vitamins, and herbal supplements. XOPENEX Inhalation Solution Concentrate may affect the way other medicines work, and other medicines may affect how XOPENEX Inhalation Solution Concentrate works.

Ask your doctor if you are not sure if any of your medicines are the kinds listed above.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

How should I use XOPENEX Inhalation Solution Concentrate?
• Read the step-by-step Instructions for Using XOPENEX Inhalation Solution Concentrate at the end of this leaflet.
• You will need to mix your XOPENEX Inhalation Solution Concentrate with sterile normal saline before you give your dose. Sterile normal saline is not included with your XOPENEX Inhalation Solution Concentrate. Ask your doctor or pharmacist about the kind of sterile normal saline you should buy.
• Use XOPENEX Inhalation Solution Concentrate exactly as your doctor tells you to. Do not change your dose without talking to your doctor first.
• Your doctor will tell you how many times and when to use your XOPENEX Inhalation Solution Concentrate.
• An adult should help a child use XOPENEX Inhalation Solution Concentrate.
• Do not use your XOPENEX Inhalation Solution Concentrate more often than your doctor tells you to.
• Get medical help right away if XOPENEX Inhalation Solution Concentrate:

• does not work as well for your asthma symptoms or
• your asthma symptoms get worse or
• you need to use your XOPENEX Inhalation Solution Concentrate more often than usual

• If you also use another medicine by inhalation, you should ask your doctor for instructions on when to use it while you are also using XOPENEX Inhalation Solution Concentrate.
• Do not mix XOPENEX Inhalation Solution Concentrate with other medicines in your nebulizer.
• Only use XOPENEX Inhalation Solution Concentrate if it is colorless. Throw away the XOPENEX Inhalation Solution Concentrate vial if the liquid medicine is not colorless.
• Do not use XOPENEX Inhalation Solution Concentrate after the expiration date on the vial.

What are the possible side effects of XOPENEX Inhalation Solution Concentrate?
XOPENEX Inhalation Solution Concentrate can cause serious side effects including:
• sudden shortness of breath (bronchospasm). Sudden shortness of breath can happen right away after using XOPENEX Inhalation Solution Concentrate.
• worsening asthma
• heart problems
• death. If you use too much XOPENEX Inhalation Solution Concentrate you can have heart or lung problems that can lead to death.
• serious allergic reactions. Call your doctor and stop using XOPENEX Inhalation Solution Concentrate right away if you have any symptoms of an allergic reaction such as:

Call your doctor or go to the nearest hospital emergency room right away if you have any of the serious side effects listed above or if you have worsening lung symptoms.The most common side effects of XOPENEX Inhalation Solution Concentrate include:
• palpitations
• chest pain
• fast heart rate
• headache
• dizziness
• tremor
• nervousness
Tell your doctor if you have any side effects that bother you or that do not go away.
These are not all the possible side effects of XOPENEX Inhalation Solution Concentrate. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Keep XOPENEX Inhalation Solution Concentrate and all medicines out of the reach of children.

General information about the safe and effective use of XOPENEX Inhalation Solution Concentrate.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use XOPENEX Inhalation Solution Concentrate for a condition for which it was not prescribed. Do not give XOPENEX Inhalation Solution Concentrate to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about XOPENEX Inhalation Solution Concentrate. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about XOPENEX Inhalation Solution Concentrate that is written for health professionals.

Read the following steps before using your XOPENEX Inhalation Solution Concentrate. If you have any questions, ask your doctor or pharmacist.

You will need to mix your XOPENEX Inhalation Solution Concentrate with sterile normal saline before you give your dose. Normal saline is not included
with your XOPENEX. Ask your doctor or pharmacist about the kind of sterile normal saline you should buy.

Step 1. Open the foil pouch by tearing the notched edge along the seam of the pouch (See Figure B). Remove the vial and use it right away.

Step 8. Sit in a comfortable, upright position. Place the mouthpiece in your mouth (See Figure H.1) or put on your face mask (See Figure H.2). Turn on the
compressor.

Figure H.1

Figure H.2

Step 9. Breathe as calmly, deeply, and evenly as possible until no more mist is seen in the nebulizer reservoir. Your treatment will take about 5 to 15 minutes. When you do not see any mist in the nebulizer reservoir, your treatment is finished.

Step 10. Clean and store your nebulizer. See the manufacturer’s instructions that come with your nebulizer for how to clean and store your nebulizer.

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

Important Safety Information

1. INDICATIONS AND USAGE

XOPENEX (levalbuterol HCl) Inhalation Solution is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease.

4. CONTRAINDICATIONS

XOPENEX Inhalation Solution is contraindicated in patients with a history of hypersensitivity to levalbuterol or racemic albuterol. Reactions have included urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema [see Warnings and Precautions (5.6)].

5. WARNINGS AND PRECAUTIONS

5.1 Paradoxical Bronchospasm

XOPENEX Inhalation Solution can produce paradoxical bronchospasm, which may be lifethreatening. If paradoxical bronchospasm occurs, XOPENEX Inhalation Solution should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new vial.

5.2 Deterioration of Asthma

Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of XOPENEX Inhalation Solution than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory
treatment, e.g., corticosteroids.

5.3 Use of Anti-Inflammatory Agents

XOPENEX Inhalation Solution is not a substitute for corticosteroids. The use of betaadrenergic agonist alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids, to the therapeutic regimen.

5.4 Cardiovascular Effects

XOPENEX Inhalation Solution, like other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients, as measured by heart rate, blood pressure, and symptoms. Although such effects are uncommon after administration of XOPENEX Inhalation Solution at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the t-wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, XOPENEX Inhalation Solution, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.5 Do Not Exceed Recommended Dose

Do not exceed the recommended dose. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.

5.6 Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of levalbuterol or racemic albuterol. Reactions have included urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving XOPENEX Inhalation Solution.

5.7 Coexisting Conditions

XOPENEX Inhalation Solution, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, hypertension, and cardiac arrhythmias; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after the use of any betaadrenergic bronchodilator.

Changes in blood glucose may occur. Large doses of intravenous racemic albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.8 Hypokalemia

As with other beta-adrenergic agonist medications, XOPENEX Inhalation Solution may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.

6. ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been observed in postapproval use of XOPENEX Inhalation Solution. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to their seriousness, their frequency of reporting, or their likely beta-mediated mechanism: angioedema, anaphylaxis, arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles), asthma, chest pain, cough increased, dysphonia, dyspnea, gastrooesophageal reflux disease (GERD), metabolic acidosis, nausea, nervousness, rash, tachycardia, tremor, urticaria.

In addition, XOPENEX Inhalation Solution, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vertigo, central nervous system stimulation, sleeplessness, headache, and drying or irritation of the oropharynx.

7 DRUG INTERACTIONS

7.1 Short-Acting Bronchodilators

Avoid concomitant use of other short-acting sympathomimetic bronchodilators or epinephrine in patients being treated with XOPENEX Inhalation Solution. If additional
adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.

7.2 Beta-blockers

Beta-adrenergic receptor blocking agents not only block the pulmonary effect of betaadrenergic agonists such as XOPENEX Inhalation Solution, but may produce severe
bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers should be considered, although they should be administered with caution.

7.3 Diuretics

The ECG changes or hypokalemia that may result from the administration of non-potassiumsparing diuretics (such as loop and thiazide diuretics) can be acutely worsened by betaagonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadmin – istration of beta-agonists with non-potassium-sparing diuretics. Consider monitoring potassium levels.

7.4 Digoxin

Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after singledose intravenous and oral administration of racemic albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving XOPENEX Inhalation Solution and digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and XOPENEX Inhalation Solution.

7.5 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants

XOPENEX Inhalation Solution should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of levalbuterol on the vascular system may be potentiated. Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled studies of XOPENEX Inhalation Solution in pregnant women. Because animal reproduction studies are not always predictive of human response, XOPENEX Inhalation Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in newborns of women treated with racemic albuterol which contains the levalbuterol isomer (active drug substance of XOPENEX Inhalation Solution). However, since multiple medications were taken during some of the pregnancies and there was no consistent pattern of anomalies, it was not possible to establish a relationship between racemic albuterol use and the occurrence of these congenital anomalies.

In animal studies, oral administration of levalbuterol HCl to pregnant New Zealand White rabbits found no evidence of teratogenicity at doses up to 25 mg/kg/day (approximately 108 times the maximum recommended daily inhalation [MRDI] dose of levalbuterol HCl for adults on a mg/m2 basis).

However, other studies demonstrated that racemic albuterol sulfate was teratogenic in mice and rabbits at doses comparable to the human therapeutic range. Pregnant mice admin –
istered racemic albuterol sulfate subcutaneously had a dose-related increased incidence of cleft palate in their fetuses (4.5% of fetuses at 0.25 mg/kg/day or greater, corresponding to approximately 0.3 times the MRDI dose, 9.3% of fetuses at 2.5 mg/kg/day, approximately 3 times the MRDI dose of levalbuterol HCl for adults on a mg/m2 basis). The drug did not induce cleft palate formation when administered subcutaneously at a dose of 0.025 mg/ kg/day (approximately 0.03 times the MRDI dose of levalbuterol HCl for adults on a mg/m2 basis). In addition, oral administration of racemic albuterol sulfate to pregnant rabbits resulted in an increased incidence of cranioschisis in fetuses (approximately 215 times the MRDI dose of levalbuterol HCl for adults on a mg/m2 basis).

Non-Teratogenic Effects: A study in which pregnant rats were dosed with radiolabeled racemic albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus.

8.2 Labor and Delivery

Because of the potential for beta-adrenergic agonists to interfere with uterine contractility, the use of XOPENEX Inhalation Solution for the treatment of bronchospasm during labor
should be restricted to those patients in whom the benefits clearly outweigh the risk.

XOPENEX Inhalation Solution has not been approved for the management of preterm labor. The benefit:risk ratio when levalbuterol HCl is administered for tocolysis has not been
established. Serious adverse reactions, including maternal pulmonary edema, have been reported during or following treatment of premature labor with beta2-agonists, including racemic albuterol.

8.3 Nursing Mothers

Plasma concentrations of levalbuterol after inhalation of therapeutic doses are very low in humans. It is not known whether levalbuterol is excreted in human milk.
Because of the potential for tumorigenicity shown for racemic albuterol in animal studies and the lack of experience with the use of XOPENEX Inhalation Solution by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Caution should be exercised when XOPENEX Inhalation Solution is administered to a nursing woman.

8.4 Pediatric Use

The safety and efficacy of XOPENEX Inhalation Solution have been established in pediatric patients 6 years of age and older in an adequate and well-controlled clinical trial [see Adverse Reactions (6) and Clinical Studies (14)]. Use of XOPENEX Inhalation Solution in children is also supported by evidence from adequate and well-controlled studies of XOPENEX Inhalation Solution in adults, considering that the pathophysiology, systemic exposure of the drug and clinical profile in pediatric and adult patients are substantially similar. Safety and effectiveness of XOPENEX Inhalation Solution in pediatric patients below the age of 6 years have not been established.

8.5 Geriatric Use

Clinical studies of XOPENEX Inhalation Solution did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Only 5 patients 65 years of age and older were treated with XOPENEX Inhalation Solution in a 4-week clinical study [see Clinical Pharmacology (12) and Clinical Studies (14)] (n=2 for 0.63 mg and n=3 for 1.25 mg). In these patients, bronchodilation was observed after the first dose on day 1 and after 4 weeks of treatment. In general, patients 65 years of age and older should be started at a dose of 0.63 mg of XOPENEX Inhalation Solution. If clinically warranted due to insufficient bronchodilator response, the dose of XOPENEX Inhalation Solution may be increased in elderly patients as tolerated, in conjunction with frequent clinical and laboratory monitoring, to the maximum recommended daily dose [see Dosage and Administration (2)].

8.6 Renal Impairment

Albuterol is known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10. OVERDOSAGE

The expected symptoms with overdosage are those of excessive beta-adrenergic receptor stimulation and/or occurrence or exaggeration of any of the symptoms listed under Adverse Reactions (6), e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min., arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and sleeplessness. Hypokalemia also may occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with the abuse of XOPENEX Inhalation Solution. Treatment consists of discontinuation of XOPENEX Inhalation Solution together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of XOPENEX Inhalation Solution.

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XOPENEX is a registered trademark of Sunovion Pharmaceuticals, Inc. and is used under license.